The penicillin binding proteins (PBPs) are ubiquitous bacterial enzymes involved in cell wall biosynthesis (reviewed in Waxman et al., 1983 Annual Review of Biochemistry 58:825-869; Georgopapadkou et al., 1983 Handbook of Experimental Pharmacology 67:1-77; and Ghuysen, 1991 Annual Review of Microbiology 45:37-67). In Staphylococcus aureus these enzymes catalyze the general reaction shown in FIG. 1 which introduces cross links into the cell wall necessary for its structural integrity. Variations on this theme are known in other bacteria (reviewed in Schleifer et al., 1972 Bacteriology Review 36:407-477). The active site serine involved in the acyl transfer reaction is the target of the .beta.-lactam antibiotics. Most bacteria posses a number of variants of this enzyme; E. coli has seven known variants labeled 1A, 1B, and 2-6. The different PBPs have different propensities towards the transpeptidation cross linking reaction shown in FIG. 1 and hydrolysis of the acyl enzyme intermediate in a proteolytic-like reaction. Those enzymes for which hydrolysis is the predominant path are also known as the (DD)-carboxypeptidases. The .beta.-lactam antibiotics inhibit the PBPs by acting as substrate analogs and forming an acyl enzyme intermediate. This acyl enzyme intermediate is resistant to subsequent hydrolysis and ties up the enzyme in a relatively long lived inactive form. This is the mechanism by which the .beta.-lactam antibiotics inhibit bacterial cell wall biosynthesis.
Bacteria have responded to the widespread use of .beta.-lactam antibiotics by evolving a class of .beta.-lactam hydrolyzing enzymes known as .beta.-lactamases. These enzymes are one of the sources of drug resistance now being observed in a number of bacterial diseases including tuberculosis, malaria, pneumonia, meningitis, dysentery, bacteriemia, and various venereal diseases. A special issue of Science (Science, Aug. 21, 1992) has been devoted to this serious public health issue. The serine .beta.-lactamases operate on .beta.-lactams in much the same fashion as do the PBPs except that the hydrolysis step to release the bound inhibitor is relatively fast. This allows the .beta.-lactamases to hydrolyze a susceptible .beta.-lactam antibiotic and render it inactive (Fisher et al., 1980 Biochemistry 19:2895-2901). A considerable amount of research has now been devoted to finding compounds which can inhibit .beta.-lactamases (reviewed in Sutherland, R., 1990 J. Reproduct. Med. 35:307-312). Most such efforts have been directed towards inhibiting .beta.-lactamases with .beta.-lactam compounds, such as clavulanic acid, so that the traditional .beta.-lactam antibiotics can survive long enough to kill the cells. Clavulanic acid is a .beta.-lactam serine .beta.-lactamase inhibitor currently being used in conjunction with .beta.-lactam antibiotics to treat resistant bacterial infections. The rapid development of resistance to this type of therapy illustrates that this strategy can only provide a temporary solution to .beta.-lactam resistance. The .beta.-lactam antibiotics, while bearing some similarity to the -(D)-Ala-(D)-Ala physiological substrate of the PBPs (Tipper & Strominger, 1965 Proc. Natl. Acad. Sci. USA 54:1133-1141), are sufficiently different in structure that it has not been difficult for .beta.-lactamases to evolve which discriminate between the .beta.-lactams and the physiological substrate for the PBPs. Given the evolutionary mobility of the .beta.-lactamases, highlighted by the evolution of zinc .beta.-lactamases (Sabath & Abraham, 1966 Biochem. J. 98:11c-13c; Saino et al., 1982 Antimicrob. Agents Chemother. 22:564-570; Sutton et al., 1987 Biochem. J 248:181-188; Iaconis & Sanders, 1990 Antimicrob. Agents Chemother. 34:44-51), the prospects for keeping ahead of the evolution of drug resistant bacteria with .beta.-lactamase inhibitors appear dim.